Pharmacokinetics and drug design

A study of the pharmacokinetic properties of a compound indicates which properties need to be modified in order to produce a more effective analogue. Consider, for example, a drug that is not suitable for development because it has too short a duration of action. The logical way forward is to determine the likely structural cause of this rapid elimination and then test analogues that either do 

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Volume of Distribution General Considerations and Applications to Experimental Pharmacokinetics and Drug Design... 

Pharmacokinetics and Drug Design Ho-Leung Fung, Bruce J. Aungst, Richard A. Morrison ... 

Herbette, L. G., Pharmacokinetic and pharmacodynamic design of lipophilic drugs based on a structural model for drug interactions with biological membranes, Pest. Sci. 35, 363-368 (1992). 

Apart from patient-specific parameters, external factors - most importantly the concomitant uptake of certain other chemicals present in diet, environment and especially other drugs - influence drug actions. Possible effects are manifold and can affect all stages of pharmacokinetic and pharmacodynamic processes in the body. Also direct interaction and inactivation of concomitantly administered substances are possible. Drug-drug interactions via modulation of metabolism present a very hot topic in pharmaceutical research and drug design. 

Pharmacokinetics and Drug Dosage Regimen Design—A Possible Application Requiring Construction and Manipulation of a Complex Model and Data Base with an Expert System... 

Many lead discovery candidates are transferred to the preclinical development process with insufficient characterization to assess their development potential. This lack of knowledge usually results in poorly designed experiments that are not data productive and that, in many cases, have to be repeated when a candidate shows unexpected toxicity, low and variable delivery, instability in formulation, or unacceptable pharmacokinetic and drug metabolism profiles. In all too many cases, the recognition of these problem areas results in termination of... 

Seydel, J. K. and Schaper, K.-J. Quantitative structure-pharmacokinetic relationships and drug design. Pharmacol. Ther. 15 131-182,1982. 

Another type of therapeutically active molecule is one designed primarily with pharmacokinetics in mind (designed to be well absorbed and to enter the central compartment readily), which can then be converted to the therapeutically active molecule in the body. These are referred to as pro-drugs. This process, called latentiation, consists of the conversion of hydrophilic drugs into lipid-soluble drugs (usually by masking hydroxyl, carboxyl, and... 

The requirements of protease inhibitors as drugs in terms of potency, pharmacokinetics, and toxicity will vary depending on the nature of the infection and the goals of therapy. At one extreme is treatment of HlV-1, a chroific infection that requires life-long therapy and full suppression of viral replication. At the other extreme is the treatment of human rhinovirus (i.e., the cold virus), where short-term treatment to blunt viremia will likely be sufficient to reduce the unwanted symptoms of a cold. In all cases, viral proteases represent very attractive targets with familiar mechanisms of catalysis that frequently allow for the design of transition state analogs and with distinct specificities from host proteases. 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

Smith, D. A., Van de Waterbeemd, H., Walker, D. K. Pharmacokinetics and Metabolism in Drug Design, 2nd edn. Methods and Principles in Medicinal Chemistry), Wiley-VCH, Weinheim, 2006. 

Finally, site-specific delivery also depends on the extent of competing processes in the biological system as well as the interaction of the drug itself with the biological system. Therefore successful design of polymeric drug delivery approaches requires a comprehensive appreciation of the pharmacology, pharmacokinetics, and pharmacodynamics involved. 

Kubinyi, H., Hydrogen bonding The last mystery in drug design in Testa, B. van de Waterbeemd, H. Folkers, G. Guy, R. (eds.), Pharmacokinetic Optimization in Drug Research, Verlag Helvetica Chimica Acta, Zurich and Wiley-VCH, Weinheim, 2001, pp. 513-524. 

Physiologically based pharmacokinetic models provide a format to analyze relationships between model parameters and physicochemical properties for a series of drug analogues. Quantitative structure-pharmacokinetic relationships based on PB-PK model parameters have been pursued [12,13] and may ultimately prove useful in the drug development process. In this venue, such relationships, through predictions of tissue distribution, could expedite drug design and discovery. 

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